The proposed research in psychoneuroimmunology is an application for renewal of a Research Scientist Award. As one means of studying CNS-immune system interactions, one goal continues to be the elaboration and mediation of behaviorally conditioned alterations in immunologic reactivity. We will investigate the possibility of conditioning enhancement of immune responses, the conditions under which one observes conditioned suppression or enhancement, and the extent to which these depend upon conditioned behavioral responses. Conditioned changes in natural killer cell activity will be studied using interferon-inducers (e.g., Poly I:C) and morphine as unconditioned stimuli (UCSs) in multiple-trial conditioning paradigms that will enable detection of possible compensatory responses. Conditioning studies that do not involve immunomodulating drugs will also be undertaken. The decreased antibody response to an antigenic stimulus administered after repeated exposures to ip injections of saline will be examined as a conditioning phenomenon. Particular emphasis will be directed to enhanced antibody responses to an immunologically neutral (conditioned) stimulus previously paired with an antigen (the UCS). Flavored drinking solutions will serve as conditioned stimuli (CSs) and antigens (e.g., keyhole limpet hemocyanin) will serve as UCSs. The generality of conditioned antibody responses will be determined by using different antigens as UCSs, and we will assess the specificity of the conditioned response (i.e., determine if conditioned changes responsible for the enhanced production of antibody are a consequence of immunologic reactions specific to the antigen or are mediated by nonspecific immunologic or neuroendocrine reactions induced by exposure to antigenic stimuli). In pursuing mediating mechanisms, the effects of conditioning on B and T cell functions and on cytokines (interleukin-1 and -2), and on norepinephrine changes in spleen and in specific regions of the hypothalamus will be examined. A second goal will be to assess the effects of immune status on behavior and the hypothesis that behavioral mechanisms can serve an in vivo immunoregulatory function. Studies of taste aversion learning in response to immunosuppressive and immunoenhancing UCSs and the voluntary consumption of solutions containing immunosuppressive and immunoenhancing agents will be assessed in lupus-prone Mrl-lpr/lpr and in congenic Mrl +/+ controls. We will also explore the direct or indirect signals emanating from the immune system that might be responsible for the observed changes in behavior. A third project will involve the effects of 'stress' on primary and secondary responses to low levels of antigenic stimuli and the temporal relationship between 'stress' and the metastatic spread of a line 1 tumor. As a byproduct of conditioning studies in animals, the role of conditioning in pharmacotherapy will be examined. Initial experiments involve the conditioned clinical and immunologic effects of prednisolone in rheumatoid arthritis patients and the effects of conditioning in the ritalin treatment of attentional deficit disorder. The proposed research will increase our understanding of the means by which behavior can serve an immunoregulatory function and provide an experimental foundation for and new approaches to the study of adaptive processes in health and in disease processes such as autoimmune diseases, infectious diseases, and AIDS which involve disordered regulation of the immune system. The research will be accomplished in new laboratory space by an expanded interdisciplinary group representing expertise in behavior, immunology, neuroendocrinology, and neuroanatomy.